Method for treating pain

ABSTRACT

Treatment and prophylaxis of pain involves administration of vitamin E combined with salicylic acid in a pharmaceutically acceptable carrier or adjuvant.

This is a divisional of application Ser. No. 08/137,940, filed Oct. 19,1993, now abandoned; which is a continuation of U.S. Ser. No.07/913,885, filed Jul. 17, 1992 now abandoned; which is a continuationof U.S. Ser. No. 07/639,418, filed Jan. 10, 1991,now U.S. Pat. No.5,153,001; which is a continuation of U.S. Ser. No. 07/290,848, filedNov. 29, 1988 abandoned; which is a continuation of U.S. Ser. No.06/870,029, filed Jun. 3, 1986, now abandoned; which is a continuationof U.S. Ser. No. 06/694,308, filed Jan. 24, 1985 now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to a new use of vitamin E.

Vitamin E is known as an antioxidant and protective vitamin forphospholipids of the cell membrane. Vitamin E maintains the permeabilityand stability of the cell membrane; cf. Lucy, Annals N.Y. Academy ofScience 203, 4 (1972). There has further been known that vitamin E has amembrane-sealing effect; cf. F. Mittelbach and G. Bodechtel, MunchnerMedizinische Wochenschrift 110 (1968) 36: 1988-1993. In erythrocytes,the simplest cells of the human body, there has been found that vitaminE provides a protective effect for the cell membrane. In tests withanimals and humans, it has been proven that anemia is a first signal ofa deficiency of vitamin E. The hemolysis of the erythrocytes willnormalize upon administration of high doses of vitamin E; cf. William J.Darbey Vitamin Horm., 26 (50) pp. 685-704 (1968) and Phelps DLPediatrics 63 (6) pp. 933-935 (1979). From these literature references,it is apparent that after the oral administration of from 200 to 800 mgof vitamin E over a period of from 1 to 4 days, the hemolysis of theerythrocytes is significantly improved as compared to patients sufferingfrom vitamin E deficiency.

Vitamin E has further been used to treat sickle cell anemia over aperiod of from 6 to 35 weeks; cf. Natt CL. Am. J. Clin. 33, pp. 968-971(1980); Natt CL. Am. J. Clin. Nutr. 32, pp. 1359-1362 (1979); Gawlik G.M., Fed. Proc. 35 (3), p. 252 (1976) and Gorash L. Bieri J. G. et al.,Univ. Conn. Farmington, Conn.

It has further been known that a daily dose of 750 mg of vitamin E overa period of from 3 to 6 months was successfully used to treatthalassemia patients, whereupon a normalization of the hemolysis of theerythrocytes was observed; cf. Kahane I. ISR. J. Med. 12 (1), pp. 11-15(1976).

Vitamin E has further been successfully applied to patients sufferingfrom an acute hepatitis or an alcoholic hepatitis having a deficiency invitamin E in serum; cf. Yoshiakawa T., Takemura S., Karo H. et al.,Japan. J. Gastrovent, 74/7, pp. 732-739 (1977). Eventually, vitamin Ehas been used to treat patients suffering from anemia due to an irondeficiency, in which treatment it caused an improvement or normalizationof the lipid metabolism in the bone marrow to occur in the course offrom 4 to 8 weeks; cf. Takoshi Itaga, Central Clinical LaboratoryNagasaki University of Medicine, Japan.

More detailed investigations of the resorption of vitamin E haveresulted in the finding that a large portion of the vitamin E isdestroyed by the gastric acid so that only part of the vitamin E candisplay its effects in the body; cf. Arthur Vogelsang in Angiology 21,pp. 275-79 (1970).

From Arzneimittel-Forschung 24, No. 2 (1974) 202 and 21, No. 3 (1971),there has been known that by means of vitamin E there results asubstantial increase in tolerance of the heart-efficient glycosides,while a relation between the effect caused by vitamin E and the dose ofvitamin E has been explicitly denied.

There has now been found that vitamin E surprisingly is suitable toenhance and improve the effects of coronary-active vasodilators and/orblood circulation promotors. These coronary-active agents, on the otherhand, promote the activity of vitamin E.

This new range of indications was not foreseeable from the knowledgeaccording to prior art and opens a new and wide field of applications ofvitamin E.

The agents, whose activities can be improved according to the presentinvention, in the first place include the coronary-efficient nitroderivatives such as nitroglycerol (glycerol trinitrate), isosorbitoldinitrate, pentaerythritol tetranitrate and mononitrate compounds. Theseagents are used for the therapy and the prophylaxis of disturbances ofcoronary blood circulation and against coronary insufficiency and in theprophylaxis of angina pectoris.

It has been found that use of these active ingredients in combinationwith a sufficient dosage of vitamin E allows the duration of treatmentto be substantially shortened. The symptoms of the diseases will be morerapidly reduced, so that after some time the applied dose of the nitrocompound can be significantly lowered.

These results were not foreseeable and enable a therapy to be applied inwhich part of the chemically active compound is substituted by asubstance of natural origin which, moreover, is present in every cell ofthe body.

Further agents whose effects can be enhanced according to the inventionare agents promoting blood circulation such as Extract. Hippocastani andβ-hydroxyethylrutoside, on the one hand, and nicotinic acid andnicotinic acid ester or derivatives thereof, respectively, such asxanthinol nicotinate and inositol nicotinate, dihydroergotoxinemethanesutfonate, dihydroergocristine methanesulfonate, anddihydroergocornine methanesulfonate, on the other hand. It has beenfound that upon application of said agents in combination with asufficient dose of vitamin E, the symptoms in many patients will befaster reduced and after some months the amounts of the vasodilatorsand/or blood circulation promoters can be lowered.

Crucial for the efficacy of vitamin E to enhance and improve the effectsof coronary-efficient and/or blood circulation-promoting agents, aboveall, is a sufficient dosage which should be at least 80 mg. Lowerdosages of vitamin E are useless, since large parts are destroyed by thegastric acid and thereby lose their activity; cf. Arthur Vogelsang, in:Angiology 21, pp. 275-279 (1970).

SUMMARY OF THE INVENTION

It is an object of the present invention to provide the use of vitamin Eto enhance and improve the coronary-effective vasodilators and/or bloodcirculation-promoting agents. Therein the dosage should be in the rangeof from 80 to 500 mg, and preferably in the range of from 150 to 400 mg.Typical combination preparations contain from 200 to 400 mg of vitaminE.

It is another object of the present invention to provide agents toeffect enhancement and improvement of the coronary-effectivevasodilators and/or blood circulation-promoting agents characterized inthat they contain vitamin E in a dose of from 80 to 500 mg, andpreferably in a dose within the aforementioned ranges.

As the vitamin E, there may be employed natural vitamin E in the form ofD-alpha-tocopherol and concentrates thereof and the respective acetatesas well as synthetic D,L-alpha-tocopherol or its acetate.

The agents according to the invention contain conventional carriers andexcipients in addition to the active ingredients and to the vitamin E.Since vitamin E is liquid at ordinary temperatures, drops and softgelatin capsules particularly offer themselves as suitable applicationforms. The other active ingredients are incorporated in the vitamin Eand, if desired, in a low-viscosity neutral oil and a solutizer such asTween in a per se known manner. In this step, more specifically, theremay be used the standard recipes of the firm Scherer, Eberbach, WestGermany.

Suitable as further carriers and excipients are lactose,polyethyleneglycol, silica and its derivatives, and emulsifiers.

The simultaneous intake of vitamin E and heart glycosides ensures theregular intake of both active ingredients. Besides, the amount of heartglycosides can be reduced during the permanent application of thevitamin E capsule combination, and thereby a digitalis intoxication orside-effects caused by the digitalis can be avoided.

When heart glycosides, such as digoxine, acetyldigoxine etc. are beingadministered, attention must be paid to that the oxygen consumption inthe heart is normal. In the case of an oxygen deficiency in the heart,the daily dose must be lowered. The oxygen consumption is economized orregulated, respectively, by the combination comprising vitamin E, sothat a constant intake of heart glycoside becomes possible, i.e. thecompatibility of the heart glycosides is increased. More specifically,due to the combination of the heart glycosides with vitamin E, aconstantly lower dosage thereof can be applied over an extended periodof time. In addition, vitamin E causes pain in the heart region to bereduced or eliminated.

There is also a possibility of alternating the intakes of a high dosageof heart glycosides in the absence of vitamin E with the combinationcomprising vitamin E and a lower digitalis dose according to theinvention. Intake of the combination comprising vitamin E and heartglycoside(s) in one capsule will shorten the duration of the treatmentand reduces the probability of a relapse and/or intoxication,respectively. Vitamin E also strengthens the heart muscle.

Vitamin E may be employed in any of its alpha-forms, in the free formsas well as in the forms of the esters. Vitamin E may be contained in anamount between 200 and 800 mg, and preferably between 300 and 600 mg, ineach capsule.

The ester to be used may be the acetate, succinate, nicotinate or anyother suitable ester. As the heart glycoside(s) there may be used, e.g.,digoxine, digitoxine, acetyldigoxine and strophantine, derivativesthereof or analogous mixtures, respectively.

As the neutral oil to be employed in the preparation of the capsulesthere may be used soybean oil or hydrogenated soybean oil, respectively,peanut oil, olive oil, triglycerides etc.

Further additives such as vitamin A or one or more vitamins of the Bseries, respectively, may be added. The capsule may also be resistent togastric juice.

There has further been unexpectedly found that vitamin E does notundergo any chemical reaction with heart glycosides, but that it is verywell compatible. Thus, according to the invention neutral oil is used asa diluent in the preparation of the capsules.

It has further been determined that vitamin E is suprisingly welltransdermally resorbable and in the course thereof comes to causeparticular effects in proximity of the site of resorption. Due to thisfinding vitamin E, more specifically, may be employed to treat heartdiseases at a lower dosage with a higher efficacy.

Thus, under one more specific aspect, it is an object of the presentinvention to provide agents for treating heart diseases which agents arecharacterized in that they contain vitamin E and optionally other activeingredients in a transdermally resorbable form.

Such agents, for example, may be in the form of an ointment containingfrom 0.5 to 20% by weight of vitamin E in conventional carriers andexcipients. Preferably, the vitamin E content is from 2 to 15% byweight.

Another possibility comprises incorporating vitamin E in a membraneplaster in an amount of from 0.05 to 5 g, wherefrom it may betransdermally resorbed. Such membrane plasters preferably contain from0.5 to 3 g of vitamin E.

According to the invention, the vitamin E may be employed asD,L-alpha-tocopherol as well as a natural D-alpha-tocopherol.

As optionally further present active ingredients, there may morespecifically be considered isosorbitol dinitrate and nitroglycerol(glycerol trinitrate), as these are also transdermally well resorbed.Further suitable are vasoditators and agents promoting blood circulationsuch as heparin sodium, Extract. Hippocastani, Extract. or Tinct.arnicae, β-hydroxyethylrutoside, salicylic acid ester, nicotinic acidester, more specifically the nicotinic acid benzylester.

The blood circulation in the heart may be enhanced by adding nifedipin.Such a combination is particularly suitable for a prophylactic treatmentof patients endangered by a cardiac infarction.

Any conventional ointment bases are suitable for the formulations of theointments, such as oil-in-water based on alcohol withpolyethyleneglycols, but also Eucerin cum aqua, Ungentum Cordes orUngentum emulsificans.

The present invention further describes the preferred use ofembrocations such as, e.g., a cream, a gel, an ointment or a lotioncontaining vitamin E as a cardiac agent.

The ointment contains as a base 70 to 30% by weight, preferably 60 to40% by weight, of water, 30 to 5% by weight, preferably 25 to 7% byweight, of Cetiol (oleyl oleate), and 30 to 2% by weight, preferably 25to 2% by weight, of cetylstearylalcohol or other aliphatic alcohols.

In the place of the cetylstearylalcohol there may also be usedaltogether or in part other emulsifying alcohols, such as, e.g.,aliphatic alcohols or wool wax alcohols or diols, respectively,stearinol, monoglycerides esterified with aliphatic acids or similarsubstances. There may also be added, e.g., paraffin or petrolatum orother suitable materials in order to render the ointment spreadable.Cetiol (oleyl oleate) may also be completely or partially replaced byother emulsifiers such as Tween 20 or Tween 80 etc..

It has been found that the best combination as a base for ointments orcreams containing vitamin E is as follows:

30 to 20% by weight of cetylstearylalcohol,

20 to 10% by weight of Cetiol (oleyl oleate),

60 to 40% by weight of water (aqua conservata).

This ointment containing vitamin E will be immediately absorbed into theskin.

It has been known that ointment bases containing water such as Ungentumemulsificans aquosum and Unguentum alkoholum lanae aquosum are suitablefor processing water-soluble active substances. However, it issurprising that ointment bases containing water to an amount ofapproximately more than 50% are very well suitable for processinglipophilic active substances such as vitamin E. Also the addition of alarger amount of emulsifier(s) such as Cetiol to, Unguentum Cordes orother ointment bases which do not contain water fail to cause the sameproperties as the above-mentioned ointment bases.

As the skin-stimulants or skin blood circulation-promoters there may bementioned Ol. juniperi, Ol. pini pumilionis (dwarf pine oil), Ol.eucalypti, Ol. rosmarinae, Tinct. camphorae (or camphor, respectively),and as vasodilators there are to be mentioned, e.g., Extract. calendulaefrom the flower and Herba calendulae.

It has been determined that these vasodilators or bloodcirculation-promoters, respectively, significantly increase the effectof vitamin E and/or shorten the duration of the treatment, respectively,and remove the pain at long sight.

At long sight, the use of vitamin E provides a stabilization orpermanent elimination of the symptoms, and, thus, the probability of arelapse to occur is very low.

The embrocations may also be prepared to be used in the liquid state,e.g. in alcohol as solutizer, such as in isopropyl alcohol or ethylalcohol. For these embrocations vitamin E is used as the freealpha-tocopherol. Further derivatives of the blood circulation-promotersof vasodilators such as, e.g., trimethylolrutoside, may be employed.

For some time, membrane plasters have also been preferred to be employedfor the application of transdermally resorbable active substances. Atypical membrane plaster of the respective type has been described, forexample, in the European Patent Application No. 80,300,038.9.

The new agents for the treatment of heart diseases are particularlysuitable to effect a rapid alleviation and removal of pain. They resultin a strengthening of the heart muscle and/or the coronary vessels,respectively. Thereby, upon a longer period of application, they alsocause the resistance to burdening of the heart to be increased which mayresult even in an increase of the physical ability of the patient.

Thus, the agents according to the present invention are particularlywell suitable for the therapy and the prophylaxis of coronarydisturbances. They are further indicated for cases of coronaryinsufficiency and for the prophylaxis of angina pectoris.

The present invention is further illustrated by the followingnon-limiting examples showing typical combinations of active substancesand dosages.

EXAMPLE 1

There are prepared capsules each containing

150 mg of xantinol nicotinate;,

400 mg of vitamin E as D,L-alpha-tocopherol acetate or alphatocopherolconcentrate; and

150 mg of soybean oil.

EXAMPLE 2

Capsules each containing

150 mg of 6-hydroxyethyl rutoside;

300 mg of vitamin E; and

150 mg of soybean oil.

EXAMPLE 3

Capsules according to Example 2, but containing

100 mg of β-hydroxyethyl rutoside;

400 mg of vitamin E;

100 mg of soybean oil; and

20 mg of Tween 80.

EXAMPLE 4

Capsules each containing

120 mg. of Extract. Hippocastani (20 mg of escin) or

200 mg of Extract. Hippocastani (35 mg of escin), respectively;

300 mg of vitamin E; and

130 mg of soybean oil.

EXAMPLE 5

Capsules each containing

250 mg of nicotinic acid;

400 mg of vitamin E; and

150 mg of soybean oil.

EXAMPLE 6

Capsules each containing

20, 40 or 60 mg of isosorbitol dinitrate on lactose as carrier;

400 mg of vitamin E (D-alpha-tocopherol acetate);

250 mg of nicotinic acid; and

200 mg of soybean oil.

EXAMPLE 7

Capsules each containing

5 mg of glycerol trinitrate on lactose as carrier;

400 mg of vitamin E (D-alpha-tocopherol acetate); and

200 mg of soybean oil.

EXAMPLE 8

Capsules each containing

0.1 mg of β-acetyldigoxin;

400 mg of D,L-alpha-tocopherol acetate; and

40 mg of soybean oil.

EXAMPLE 9

Capsules each containing

0.2 mg of β-acetyldigoxin;

400 mg of D,L-alpha-tocopherol acetate; and

40 mg of soybean oil.

EXAMPLE 10

Capsules each containing

0.25 mg of digoxin;

500 mg of D-alpha-tocopherol acetate;

100 mg of soybean oil; and

10,000 I.U. of vitamin A palmitate.

EXAMPLE 11

Capsules each containing

0.05 mg of digoxin;

400 mg of D,L-alpha-tocopherol acetate;

13.75 mg (25,000 I.U.) of vitamin A palmitate;

12.40 mg of peanut oil; and

50 mg of soybean oil.

EXAMPLE 12

Capsules each containing

0.07 mg of digoxin;

350 mg of D,L-alpha-tocopherol acetate; and

50 mg of soybean oil.

EXAMPLE 13

A heart ointment containing vitamin E was prepared as follows: Eucerincum aqua is stirred with D-alpha-tocopherol or D,L-alpha-tocopherol togive an ointment, so that 7.5 g of vitamin E are contained per 100 g ofointment.

EXAMPLE 14

In the same manner as described in Example 13, an ointment containing7.5 g of D-alpha-tocopherol and 1.0 g of isosorbitol dinitrate per 100 gof ointment is obtained.

EXAMPLE 15

In the same manner as described in Example 13, an ointment containing8.5 g of D-alpha-tocopherol per 100 g of ointment is obtained.

EXAMPLE 16

In the same manner as described in Example 13, an ointment containing 7g of D-alpha-tocopherol and 10.000 I.U. of heparin sodium per 100 g ofointment is obtained.

EXAMPLE 17

In the same manner as described in Example 13, an ointment containing9.5 g of D-alpha-tocopherol and 2 g Extract. Hippocastani standardizedto at least 8% of escin per 100 g of ointment is obtained.

EXAMPLE 18

Capsules each containing

0.1 mg of β-acetyldigoxin;

400 mg of D,L-alpha-tocopherol acetate;

25,000 I.U. of vitamin A palmitate; and

40 mg of soybean oil.

EXAMPLE 19

Capsules each containing

0.2 mg of β-acetyldigoxin;

400 mg of D,L-alpha-tocopherol acetate;

25,000 I.U. of vitamin A palmitate; and

40 mg of soybean oil.

EXAMPLE 20

Capsules each containing

0.25 mg of digoxin;

500 mg of D-alpha-tocopherol acetate;

50,000 I.U. of vitamin A palmitate; and

100 mg of soybean oil.

EXAMPLE 21

Capsules each containing

10 mg of nifedipin;

400 mg of D,L-alpha-tocopherol acetate;

8,000 I.U. of vitamin A palmitate; and

200 mg of soybean oil.

EXAMPLE 22

Capsules each containing

10 mg of nifedipin;

400 mg of D-alpha-tocopherol acetate;

8,000 I.U. of vitamin A palmitate; and

200 mg of soybean oil.

EXAMPLE 23

Capsules each containing

20.0 mg of nifedipin;

500 mg of D-alpha-tocopherol acetate;

1,000 I.U. of vitamin A acetate; and

220 mg of soybean oil.

EXAMPLE 24

Capsules each containing

20.0 mg of nifedipin;

500 mg of D-alpha-tocopherol acetate; and

220 mg of soybean oil.

EXAMPLE 25

Capsules each containing

20.0 mg of nifedipin;

500 mg of D-alpha-tocopherol acetate;

6 mg of β-carotene; and

220 mg of soybean oil.

EXAMPLE 26

Ointment containing

10 g of D-alpha-tocopherol;

50,000 I.U. of heparin sodium; and

100 g of ointment base comprising

22 parts of cetylstearylalcohol,

18 parts of Cetiol and

60 parts of water (aqua conservata).

EXAMPLE 27

Ointment containing

7 g of vitamin E (D-alpha-tocopherol);

1 g of nicotinic acid benzyl ester;

1 g of camphor; and

100 g of ointment base comprising

17 parts of cetylstearylalcohol,

8 parts of white petrolatum,

15 parts of cetiol

60 parts of water (aqua conservata).

EXAMPLE 28

Ointment containing

7 g of vitamin E and

15 g of Tinct. calendulae; and

100 g of ointment base comprising

13 parts of wool wax alcohol;

2 parts of cetylstearylalcohol;

20 parts of Cetiol;

5 parts of paraffin;

50 parts of water (aqua conservata).

EXAMPLE 29

Ointment containing

8 g of vitamin E (D,L-alpha-tocopherol);

1.5 g of rosemary oil;

1 g of Extract. Hippocastani (standardized to at least 8% of escin);

1 g of juniper oil; and

100 g of ointment base according to Example 26.

EXAMPLE 30

Solution comprising

5 g of vitamin E (D-alpha-tocopherol);

1 g of dwarf pine oil (Ol. pini pumilionis);

1 g of eucalyptus oil;

1 g of juniper oil; and

100 g of isopropyl alcohol;

EXAMPLE 31

Ointment containing

7 g of D,L-alpha-tocopherol concentrate;

2 g of Tinct. arnicae;

2 g of salicylic acid β-hydroxyethylester; and

100 g of ointment base according to Example 26.

EXAMPLE 32

Solution comprising

7.0 g of vitamin E;

1.0 g of dwarf pine oil;

1.0 g of Tinct. arnicae; and

100 g of isopropyl alcohol.

EXAMPLE 33

Ointment containing

9.0 g of vitamin E and

20.0 g of Tinct. calendulae and

100 g of ointment base according to Example 26.

What is claimed is:
 1. A method of treating or prophylaxis of painassociated with disease selected from the group consisting of heartdiseases, coronary circulatory disorders, and cardiac insufficiencycomprising orally administering to a mammal in need thereof acomposition comprising 80 to 800 mg vitamin E, an effective amount ofsalicylic acid ester, and a pharmaceutically acceptable carrier oradjuvant.